Authors’ Reply: Endopeptidase Therapy for Anti-Glomerular Basement Membrane Disease: Beware of Anti-Hinge Antibodies!
Authors: Mårten Segelmark, Christian Kjellman
Journal: Journal of the American Society of Nephrology (2022)

First, we would like to thank Borza and Manral for their interest in our study GOOD-IDES-01.1 In this study, 15 patients with anti–glomerular basement membrane antibodies and an eGFR <15 ml/min were given a single dose of 0.25 mg/kg imlifidase on top of standard of care. This led to a rapid decline of circulating autoantibodies and, at 6 months, ten patients were alive with functioning native kidneys. In their letter, Borza and Manral suggest the reason why more patients did not have their kidney function salvaged could be due to anti-hinge antibodies preferentially reacting with neoepitopes formed after IgG cleavage with imlifidase. When trying to perform a post hoc analysis of the treatment failures, it is important to know that one more patient was able to stop dialysis after the end of the study, at 8 months after imlifidase treatment. Thus, at 1 year, 73% of patients were alive and free of dialysis. There are several possible reasons why not all of the patients responded to treatment, including severity of damage at the start of treatment, tubulointerstitial fibrosis, other pathogenic mechanisms (i.e., T cells, anti–neutrophil cytoplasm antibodies), magnitude of autoantibody rebound, epitope specificity of the autoantibodies at rebound, and anti-hinge antibodies. The significance of anti-hinge antibodies has been discussed in the literature (as referenced by Borza and Manral) and, although these antibodies can be detected in vivo and have the ability to restore the Fc-function of fragmented antibodies in vitro, the effect of anti-hinge antibodies after imlifidase treatment is likely NS during the early course after treatment because the levels are low, they are cleaved by imlifidase, and they are efficiently neutralized by the high levels of F(ab′)2 resulting from the imlifidase treatment. We previously measured F(ab′)2 fragments by both ELISA and SDS-PAGE and the data show that fragments are readily detectable for approximately 1 week using both methods.2 During the period before rebound of IgG, any uncleaved anti-hinge antibody must be saturated by F(ab′)2 fragments. The possibility that anti-hinge antibodies rebound at high levels and react with tissue-bound F(ab′)2 fragments was a theoretic concern before our study, and a major reason why moderate-to-severe lung hemorrhage was an exclusion criterion in the study. However, in those patients with mild lung engagement that were included in the study, we observed no indication of such events. We are grateful for the suggestion of measuring anti-hinge antibodies before treatment and at rebound, but we are inclined to be more concerned over rebound of anti–glomerular basement membrane antibodies. Disclosures C. Kjellman reports being employed by, having ownership interest in, and having patents or royalties with Hansa Biopharma AB. M. Segelmark reports having consultancy agreements with AstraZeneca, Hansa Biopharma AB, Toleranzia AB, and Vifor Pharma; receiving research funding from Hansa Biopharma AB; and spouse being employed by Nanoecho AB Sweden. Funding None.